Idiopathic inflammatory myopathies (IIMs), collectively called myositis, are a group of rare, systemic autoimmune diseases. The skeletal muscle is attacked by cells of the immune system consequently leading to proximal muscle weakness and in many individuals extra-muscular manifestations including fever, interstitial lung disease, and arthritis or skin rash. Several forms of the disease can be distinguished based on clinical features, autoantibody profiles and muscle histopathology. The commonly used nomenclature includes polymyositis, dermatomyositis, inclusion body myositis (IBM) and immune mediated necrotizing myopathy (Dalakas et al. The immunopathologic and inflammatory differences between dermatomyositis, polymyositis and sporadic inclusion body myositis. Curr Opin Neurol 1996, 9(3):235-239; Greenberg. Proposed immunologic models of the inflammatory myopathies and potential therapeutic implications. Neurology 2007, 69(21):2008-2019; Ernste et al. Idiopathic inflammatory myopathies: current trends in pathogenesis, clinical features, and up-to-date treatment recommendations. Mayo Clin Proc 2013, 88(1):83-105; Emslie-Smith et al. Necrotizing myopathy with pipestem capillaries, microvascular deposition of the complement membrane attack complex (MAC), and minimal cellular infiltration. Neurology 1991, 41(6):936-939; Bronner et al. Necrotising myopathy, an unusual presentation of a steroid-responsive myopathy. J Neurol 2003, 250(4):480-485; Liang et al. Necrotizing autoimmune myopathy. Curr Opin Rheumatol 2011, 23(6):612-619; Grable-Esposito et al. Immune-mediated necrotizing myopathy associated with statins. Muscle Nerve 2010, 41(2):185-190; Christopher-Stine et al. A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy. Arthritis Rheum 2010, 62(9):2757-2766; Griggs et al. Inclusion body myositis and myopathies. Ann Neurol 1995, 38(5):705-713).
More recently a number of studies suggest that the autoantibody status of myositis patients defines more specific disease clinical phenotypes including extramuscular organ involvement and treatment response. Myositis-specific autoantibodies can be detected in the serum of approximately 50-60% of myositis patients. The most frequent specificities are autoantibodies against aminoacyl transfer RNA (tRNA) synthetases including histidyl-tRNA synthetase (Jo-1) (Mathews et al. Myositis autoantibody inhibits histidyl-tRNA synthetase: a model for autoimmunity. Nature 1983, 304(5922):177-179); approximately 20-25% of patients with IIM show this reactivity (Gunawardena et al. Myositis-specific autoantibodies: their clinical and pathogenic significance in disease expression. Rheumatology (Oxford) 2009, 48(6):607-612; Targoff: Myositis specific autoantibodies. Curr Rheumatol Rep 2006, 8(3):196-203). Other frequently detected autoantibodies are anti-TIF1 gamma (p155/140), anti-Mi-2, anti-SRP, and anti-MDA-5 (CADM-140) antibodies (Betteridge et al. Novel autoantibodies and clinical phenotypes in adult and juvenile myositis. Arthritis Res Ther 2011, 13(2):209; Gunawardena et al. Clinical associations of autoantibodies to a p155/140 kDa doublet protein in juvenile dermatomyositis. Rheumatology (Oxford) 2008, 47(3):324-328; Targoff et al. The association between Mi-2 antibodies and dermatomyositis. Arthritis Rheum 1985, 28(7):796-803; Targoff et al. Antibody to signal recognition particle in polymyositis. Arthritis Rheum 1990, 33(9):1361-1370; Gono et al. Clinical manifestation and prognostic factor in anti-melanoma differentiation-associated gene 5 antibody-associated interstitial lung disease as a complication of dermatomyositis. Rheumatology (Oxford) 2010, 49(9):1713-1719). All these autoantibodies are, however, directed against ubiquitously expressed proteins of the cytoplasm or the cell nucleus. Until now, little is known about autoantigens predominantly expressed in the skeletal muscle although a few targets have recently been described as biomarkers for the IIM subtype IBM (Salajegheh et al. Autoantibodies against a 43 KDa muscle protein in inclusion body myositis. PLoS One 2011, 6(5):e20266; Larman et al. Cytosolic 5′-nucleotidase 1A autoimmunity in sporadic inclusion body myositis. Ann Neurol 2013, 73(3):408-418). Identifying and characterizing novel muscle-specific autoantigens involved in immune-mediated processes during muscle dysfunctions could help to explain how a chronic autoimmune attack of the skeletal muscle initiates and progresses.
Four-and-a-half-LIM domain 1 (FHL1) is a member of the FHL family of proteins characterized by four and a half highly conserved LIM domains. LIM domains are cysteine-rich, tandem zinc finger motifs mediating protein-protein interactions. Several spliced variants of FHL1 have been identified containing additional domains resulting in differential intracellular localization, protein interactions and functions (Shathasivam et al. Genes, proteins and complexes: the multifaceted nature of FHL family proteins in diverse tissues. J Cell Mol Med 2010, 14(12):2702-2720). The major isoforms are FHL1 isoform A (containing 4 and ½ LIM domain, predicted molecular size 32 kDa), isoform B (containing 3 and ½ LIM domain, a nuclear localization and export sequences and a binding site for RBP-J (recombination signal binding protein for immunoglobulin kappa J region) region, predicted molecular size 36 kDa) and the short isoform C (containing 2 and ½ LIM domain A and a RBP-J region, predicted molecular size 22 kDa). A variety of interactions with different proteins have been described, either with components of the cytoskeleton to scaffold cytoskeletal and signalling complexes or in the nucleus to regulate gene transcription. Since FHL1 is predominantly expressed in the skeletal muscle, all of these protein interactions translate into a multifunctional role of FHL1 in muscle growth and differentiation, structural maintenance including assembly of the sarcomere as well as cell signalling, although the precise molecular mechanisms are largely unknown (Shathasivam ibid; McGrath et al. Four and a half LIM protein 1 binds myosin-binding protein C and regulates myosin filament formation and sarcomere assembly. J Biol Chem 2006, 281(11):7666-7683; Cowling et al. Four and a half LIM protein 1 gene mutations cause four distinct human myopathies: a comprehensive review of the clinical, histological and pathological features. Neuromuscul Disord 2011, 21(4):237-251). Most importantly, several genetic FHL1 mutations have been identified that are causative for numerous different X-linked myopathies such as reducing body myopathy (RBM) (Schessl et al. Familial reducing body myopathy with cytoplasmic bodies and rigid spine revisited: identification of a second LIM domain mutation in FHL1. Neuropediatrics 2010, 41(1):43-46; Schessl et al. Clinical, histological and genetic characterization of reducing body myopathy caused by mutations in FHL1. Brain 2009, 132(Pt 2):452-464; Schessl et al. Proteomic identification of FHL1 as the protein mutated in human reducing body myopathy. J Clin Invest 2008, 118(3):904-912; Shalaby et al. Novel FHL1 mutations in fatal and benign reducing body myopathy. Neurology 2009, 72(4):375-376), X-linked myopathy characterized by postural muscle atrophy (XMPMA) (Schoser et al. Consequences of mutations within the C terminus of the FHL1 gene. Neurology 2009, 73(7):543-551; Windpassinger et al. An X-linked myopathy with postural muscle atrophy and generalized hypertrophy, termed XMPMA, is caused by mutations in FHL1. Am J Hum Genet 2008, 82(1):88-99), scapuloperoneal myopathy (SPM) (Chen et al. A novel mutation in FHL1 in a family with X-linked scapuloperoneal myopathy: phenotypic spectrum and structural study of FHL1 mutations. J Neurol Sci 2010, 296(1-2):22-29) and Emery-Dreifuss muscular dystrophy (EDMD) (Gueneau et al. Mutations of the FHL1 gene cause Emery-Dreifuss muscular dystrophy. Am J Hum Genet 2009, 85(3):338-35). These diseases are rare hereditary muscle disorders that mainly affect children or individuals of young age. Although FHL1-associated myopathies share some overlapping pathological features, they differ in respect to severity of muscle weakness ranging from development of scoliosis, spinal rigidity, progressive muscle loss till complete loss of ambulation and death caused by respiratory or heart failure (Cowling ibid). A molecular explanation might be protein instability because of a possible destruction of the zinc finger motif consequently leading to protein aggregation and degradation (Schessl ibid). All these studies indicate that FHL1 is critical for a healthy skeletal muscle structure and functionality.